This invention relates to compounds useful in elevating high density lipoprotein, the xe2x80x9cgoodxe2x80x9d cholesterol. Compounds of this invention increase plasma levels of HDL in a cholesterol fed rat model and as such these compounds may be useful for treating diseases such as atherosclerosis.
It is widely beleived that HDL is a xe2x80x9cprotectivexe2x80x9d lipoprotein [Gloria Lena Vega and Scott Grundy, Current Opinion in Lipidology, 7, 209-216 (1996)] and that increasing plasma levels of HDL may offer a direct protection against the development of atherosclerosis. Numerous studies have demonstrated that both the risk of coronary heart disease (CHD) in humans and the severity of experimental atherosclerosis in animals are inversely correlated with serum HDL cholesterol (HDL-C) concentrations (Russ et al., Am. J. Med., 11 (1951) 480-493; Gofman et al, Circulation, 34 (1966) 679-697; Miller and Miller, Lancet, 1 (1975) 16-19; Gordon et al., Circulation, 79 (1989) 8-15; Stampfer et al., N. Engl. J. Med., 325 (1991) 373-381; Badimon et al., Lab. Invest., 60 (1989) 455-461). Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke. Angiographical studies have shown that elevated levels of some HDL particles in humans appears to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (Miller et al., Br. Med. J., 282 (1981) 1741-1744).
There are several mechanisms by which HDL may protect against the progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al., Arteriosclerosis, 6 (1986) 434-441). Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissues of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res., 9 (1968) 155-167). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al., Circulation, 66 (Suppl. II) (1982) 102; MacKinnon et al., J. Biol. Chem., 261 (1986) 2548-2552). In addition, HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem., 253 (1978) 8034-8041; Lagocki and Scanu, J. Biol. Chem., 255 (1980) 3701-3706; Schaefer et al., J. Lipid Res., 23 (1982) 1259-1273). Accordingly, agents which increase HDL cholesterol concentrations are useful as anti-atherosclerotic agents, particularly in the treatment of dyslipoproteinemias and coronary artery disease.
Takagi et al., U.S. Pat. No. 5,608,109, discloses agricultural and horticultural insecticidal compounds according to formula A below where Ar and R2 is optionally substituted phenyl, R1 and R3 are independently hydrogen, alkyl, alkenyl or alkynyl, and R4 and R5 are independently hydrogen or alkyl.
The compounds of this invention which elevate plasma levels of HDL cholesterol have the general structure A 
wherein:
R1, R2, and R3 are independently hydrogen, C1-C6 alkyl, phenyl or xe2x80x94(CH2)1-6 phenyl where phenyl is optionally substituted by halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 alkoxycarbonyl, xe2x80x94CO2H or OH;
R4 and R5 are independently hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, xe2x80x94(CH2)0-6Ar1 where Ar1 is phenyl, naphthyl, furanyl, pyridinyl or thenyl and Ar1 can be optionally substituted by halogen, cyano, nitro, C1-C6 alkyl, phenyl, C1-C6 alkoxy, phenoxy, trifluoromethyl, C1-C6 alkoxycarbonyl, xe2x80x94CO2H or OH, or R4 and R5 together with the nitrogen to which R4 and R5 are attached form a ring containing 4-7 carbon atoms;
and Ar is phenyl, naphthyl, furanyl, pyridinyl or thienyl which may be optionally substituted by halogen, cyano, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, C1-C6 alkoxy, phenoxy, trifluoromethyl, C1-C6 alkoxycarbonyl, xe2x80x94CO2H or OH; with the proviso that Ar and R2 cannot simultaneously be optionally substituted phenyl when the R1 and R3 are independently hydrogen or alkyl.
The compounds are tested in vivo in rats fed cholesterol-augmented rodent chow for 8 days according to the test protocol and blood from the rats analyzed for HDL cholesterol.
The compounds of this invention are prepared by reacting 4-oxo-4-arylbutyric acid amides with an appropriately substituted thiosemicarbazide according to Scheme I. The intermediate 4-oxo-4-arylbutyric acid amides are conveniently prepared by the routes shown in Scheme II by reacting an amine of the formula HNR4R5 with either a 4-aryl-4-oxobutyric acid or a xcex3-aryl-xcex3-butyrolactone. Specific examples are given in the Experimental Section.
Scheme I: Preparation of Title Compounds 
Scheme II: Preparation of Intermediate 4-oxo-4-phenylbutyric Acid Amides
(1) Route A to Ketoamide 1
(2) Route B to Ketoamide 1